KOAL: Knowledge-Driven Prostate Cancer Grading with Ordinal-Aware Learning
Authors: Zheng Guo, Jiaqi Cui, Haocheng Xiong, Jize Han, Bo Liu, Qianwen Zhang, Rui Chen, Yan Wang
Organizations: School of Computer Science, Sichuan University, China · China Mobile (Suzhou) Software Technology Company Limited, China · Shanghai Changhai Hospital, Naval Medical University, China · Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
Abstract
Non-invasive prediction of Gleason Grade Group (GGG) in prostate cancer using multiparametric MRI (mpMRI) is clinically vital for reducing unnecessary biopsies. Existing GGG prediction methods face two major limitations. First, they often overlook non-image information critical for GGG prediction, including age, prostate-specific antigen (PSA), and expert priors embedded in radiology reports. Second, they tend to oversimplify GGG as flat categorical labels, failing to account for its intrinsic hierarchy of primary and secondary Gleason patterns. To this end, we propose a novel Knowledge-Driven Ordinal-Aware Learning (KOAL) framework with three synergistic modules. Specifically, the Clinical-Context Modulation (CCM) module uses clinical variables (e.g., age and PSA) to dynamically modulate discriminative image representations. The Knowledge-Guided Prototype Alignment (KGPA) module leverages an LLM to extract group-specific expert knowledge from training radiology reports and clinical guidelines, producing offline semantic anchors describing grade-specific radiological findings without requiring patient-specific reports at inference. Through prototype contrastive alignment, patient-specific mpMRI representations are matched with these anchors to promote pathology-aligned representation learning. The Hierarchical Ordinal-aware Constraints (HOC) module decouples primary and secondary Gleason pattern prediction and maps their probabilistic outputs to GGG via a Differentiable Bio-logic Mapping Layer (DBML), ensuring pathological grading consistency. Experiments on public PI-CAI and in-house datasets demonstrate that KOAL outperforms state-of-the-art methods. Code is available at: https://github.com/Gother-GZ/KOAL.
Biochemical recurrence (BCR) after radical prostatectomy is a critical endpoint in prostate cancer, yet risk stratification relies almost entirely on variables dominated by Gleason grade. Whether H&E whole slide images (WSIs) carry prognostic signal beyond grade, and whether multiple instance learning (MIL) can recover it, remains unsettled. A key obstacle is that many pipelines select model checkpoints on the evaluation fold, artificially inflating concordance. We construct a rigorous benchmark on TCGA-PRAD (487 patients, 101 BCR events) using strict out-of-fold scoring over five-fold cross-validation repeated across five seeds. The choice of MIL aggregator (ABMIL, CLAM, TransMIL, PatchGCN) has little effect (C-index 0.61-0.64 with UNI2-h), while the feature extractor is the dominant factor (ResNet50 0.566 versus pathology foundation models up to 0.639). A clinical Cox model on grade, stage, and age reaches 0.687; no imaging-only model significantly outperforms it (p > 0.10). We introduce Grade-Disentangled MIL (GD-MIL), a gated-attention MIL encoder trained with a gradient-reversal grade adversary that encourages the slide representation to be invariant to Gleason grade before late fusion with clinical variables. GD-MIL achieves C-index 0.704, significantly outperforming both the clinical baseline (delta-c = +0.029, p = 0.0005) and the best imaging-only model (delta-c = +0.062, p = 0.039), suggesting H&E morphology contains prognostic information complementary to grade. A median risk split yields log-rank p < 0.0001 separation in BCR-free survival (~20% vs ~70% at five years).
Deep learning models for prostate MRI-based cancer grading may encode clinical covariates that either reflect useful disease-related signal or non-generalising shortcut information, but their role is usually assumed. We propose a causal-reasoning framework for probing covariate dependence in MRI-based International Society of Urological Pathology (ISUP) Grade Group prediction. Rather than treating mpMRI as a direct cause of grade, we model MRI appearance and ISUP grade as observations of latent tumour pathology, and test whether candidate clinical variables act as nuisance correlates, disease-related proxies, or irrelevant covariates in the learned representation. We implement this using an adversarial framework that suppresses the decodability of individual clinical covariate at a time while preserving MRI-based grade prediction. The approach is developed and evaluated on 2,903 prostate MRI examinations, with external validation on 576 patients. We report a set of interesting and previously under-explored imaging-to-clinical-variable interactions in the context of deep learning generalisation. For examples, in binary ISUP Grade Group ≥2 classification, suppressing age, BMI, and alcohol use improved AUC by 1.23%, 0.84%, and 1.42%, respectively (all p < 0.05), suggesting reduced non-generalising covariate information; In contrast, suppressing PSA and prostate volume degraded AUC by 1.91% and 7.61% (all p < 0.001), indicating that these variables carried task-relevant signal. These findings show that adversarial covariate suppression can provide a practical representation-level analysis for distinguishing potentially harmful dependence from informative signal in prostate MRI grading models.
In prostate cancer histopathology, the Gleason Score is determined by the most frequent (Primary) and second most frequent (Secondary) Gleason patterns within a whole-slide image. Although these slide-level labels are routinely available in clinical practice, instance-level Gleason annotations are rarely provided, making patch-level learning challenging. We propose a Multiple Instance Learning (MIL) framework that estimates instance-level Gleason patterns from slide-level Primary and Secondary labels. The proposed method formulates instance-level learning according to the clinical definition of the Gleason Score by aggregating instance predictions into class counts and explicitly modeling the Primary pattern, Secondary pattern, and their dominance. Experimental results demonstrate that the proposed formulation enables effective instance-level learning and outperforms existing MIL approaches on the SICAP-MIL dataset.